Paediatric implications for some adult disorders : Scientific proceedings of the 4th Unigate Workshop, held at the Royal Academy of Physicians, St. Andrews Place, London, N.W. 1, May 1976 / edited by Donald Barltrop.
- Unigate Paediatric Workshop 1976 : Royal College of Physicians)
- Date:
- 1977
Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Credit: Paediatric implications for some adult disorders : Scientific proceedings of the 4th Unigate Workshop, held at the Royal Academy of Physicians, St. Andrews Place, London, N.W. 1, May 1976 / edited by Donald Barltrop. Source: Wellcome Collection.
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![Metabolie eause s of renal stone formation 19 (EC 2.4.2.10) and OMP-decarboxylase (EC 4.1.1.23). Only OMP-decarboxylase is deficient in the Type II variant. Geneties Both disorders are transmitted in an autosomal recessive manner, and are genetically distinct from one another (Fox, O'Sullivan and Firkin, 1969; Fox et al, 1973). The precise basis for the double enzyme defect in Type I hereditary orotic aciduria is uncertain. A mutation of a regulator gene controlling the activity of an Operon which includes structural genes regu¬ lating the synthesis of both enzymes has been sug¬ gested. A more likely hypothesis is that the two enzymes are separate polypeptide chains of the same protein, the synthesis of each polypeptide chain being directed by a different structural gene. This would explain the occurrence of Type II hereditary orotic aciduria on the basis of a mutation affecting one polypeptide chain only, the Type I variant arising from a different mutation which reduced the activity of the second chain by a secondary effect, perhaps by preventing normal protein-protein interactions between the two chains. Worthy, Grobner and Kelley (1974) have recently obtained evidence compatible with a structural gene mutation in a case of Type I hereditary orotic aciduria. Clinieal features As far as can be judged from the small number of reports available. Types I and II cases are clinically indistinguishable. The infants are normal at birth and typically present between the ages of 3 and 6 months with failure to thrive and anaemia. The peripheral blood shows hypochromia, anisocytosis, poikilocytosis and granulocytopoenia, but normal numbers of platelets. The bone marrow is megaloblastic, but folate and vitamin Bi2 levels are normal, and there is no glos¬ sitis. Mental and physical growth are stunted, and the hair is sparse, nail growth poor, and the spleen enlarged. The urine contains large amounts of orotic acid [1-0-1-5 g (6'46-9-68 mmol) per 24 hr], which crystal¬ lizes and this may cause the patient to present with haematuria and renal pain. Presentation in later childhood with megalo¬ blastic anaemia and urinary symptoms but normal mental and physical growth has been reported. The diagnosis is confirmed biochemically by identifying the long needle-like crystals in the urine as orotic acid on the basis of their U-V absorption spectra, and by measuring the orotic acid excretion (Huguley et al., 1959; Rosenbloom and Seegmiller, 1964; Rogers and Porter, 1968; White, 1969). Further confirmation is obtained by measuring the activities of OPRT and OMP-decarboxylase in erythrocytes, leukocytes or cultured skin fibroblasts. The enzyme defect has also been demonstrated in liver tissue obtained by percutaneous biopsy. Treatment Oral replacement therapy with uridine in divided doses of 100-150 mg/kg body weight per day cures the anaemia, promotes normal growth, and abolishes the abnormal orotic aciduria (Becroft and Phillips, 1965). The prognosis for intelligence is less certain. This might be improved by beginning treatment immediately after birth, and as OPRT and OMP decarboxylase are present in cultured amniotic fluid cells, it should be possible to identify an affected child prenatally in a family where a case has already occurred. Anuria or severe oliguria due to urinary obstruc¬ tion should be treated by inducing a vigorous di¬ uresis of alkaline urine. This can be supplemented if necessary by irrigating the renal pelves and ureters through ureteric catheters. References Archer, H.E., Dormer, A.E., Scowen, E.F. & Watts, R.W.E. (1958) The aetiology of primary hyperoxaluria. British Medical Journal, 1, 175. Atkins, G.L., Dean, B.M,, Griffin, W.J., Scowen, E.F. & Watts, R.W.E. (1965) Quantitative aspects of ascorbic acid metabolism in patients with primary hyperoxaluria. Clinical Science, 29, 305. Becker, M.A., Meyer, L.J., Wood, A.W. & Seeomiller, J.E. (1973) Purine overproduction in man associated with increased phosphoribosylpyrophosphate synthetase acti¬ vity. Science, 179, 1123. Becker, M.A. & Seegmiller, J.E. (1974) Genetic aspects of gout. Annual Review of Medicine, 25, 15. Becroft, D.M.O. & Phillips, L.l. (1965) Hereditary orotic aciduria and megaloblastic anaemia: a second case, with response to uridine. British Medical Journal, 1, 547. BosTRÖM, H. & Hambraeus, L. (1964) Cystinuria in Sweden VII. Clinical, histopathological and medico-social aspects of the disease. Acta Medica Scandinavica, Supplement 41, 1. Bourke, е., Erindt, G., Flynn, P. & Schreiner, G.E. (1972) Primary hyperoxaluria with normal alpha-keto- glutarate : glyoxylate carbol igase activity. Annals of Inter¬ nal Medicine, 76, 279. Brodehl, J., Gellisen, К. & Kowalewski, S. (1967) Iso¬ lierter Defekt der tubulären Cystin-Rückresorption in einer familie mit idiopathischem Hypoparathyroidismus. Klinische Wochenschrift, 45, 38. Cartier, P. & Hamet, M. (1974) Une nouvelle maladie métabolique; le deficit complet en adenine phosphoribosyl- transferase avec lithiase de 2,8-dihydroxyadenine. Comptes Rendus Hébdomadaires des Séances de L'académie de Sciences, 279, Series D, 883. Chalmers, R.A., Johnston, M., Pallis, C. & Watts, R.W.E. (1969a) Xanthinuria with myopathy. Quarterly Journal of Medicine, (N.S.) 38, 493. Chalmers, R.A., Watts, R.W.E., Pallis, C., Bitensky, L. & Chayen, J. (1969b) Crystalline deposits in striped muscle in xanthinuria. Nature, London, 221, 170. Crawhall, J.C., Scowen, E.F. & Watts, R.W.E. (1959) Conversion of glycine to oxalate in primary hyperoxaluria. Lancet, ii, 806.](https://iiif.wellcomecollection.org/image/b18031298_0032.JP2/full/800%2C/0/default.jpg)
