Hereditary orotic aciduria

Figure 7-20. De novo synthesis of purines and pyrimidines. Ribonucleotide reductase (R.R.) catalyzes the reduction of the ribose moiety in ADP, GDP, and CDP to deoxyribose. The source of each of the atoms is indicated in the boxes at the bottom of the figure. In hereditary orotic aciduria, the enzymes converting orotate to UMP are defective ( ).

In hereditary orotic aciduria, orotic acid is excreted in the urine because the enzymes that convert it to uridine monophosphate, orotate phosphoribosyl transferase and orotidine 5 -phosphate decarboxylase, are defective (see Figure 7-20). Pyrimidines cannot be synthesized, and therefore, normal growth does not occur. Oral administration of uridine bypasses the metabolic block and provides the body with a source of pyrimidines. 

Hereditary orotic aciduria is a rare autosomal recessive trait. In this disorder, both orotate phosphoribosyltrans-ferase and orotidine-5 -phosphate decarboxylase activities (reactions 5 and 6 in Figure 27-26) are markedly deficient. Recall that these activities occur on the polypeptide Pyr 5,6. 

Deficiency of folate or vitamin Bn can cause hematological changes similar to hereditary orotic aciduria. Folate is directly involved in thymidylic acid synthesis and indirectly involved in vitamin Bn synthesis. Orotic aciduria without the characteristic hematological abnormalities occurs in disorders of the urea cycle that lead to accumulation of carbamoyl phosphate in mitochondria (e.g., ornithine transcarbamoylase deficiency see Chapter 17). The carbamoyl phosphate exits from the mitochondria and augments cytosolic pyrimidine biosynthesis. Treatment with allopurinol or 6-azauridine also produces orotic aciduria as a result of inhibition of orotidine-5 phosphate decarboxylase by their metabolic products. 

Fig. 41.16. Conversion of carbamoyl phosphate and aspartate to UMP. The defective enzymes in hereditary orotic aciduria are indicated ( h).

Hereditary orotic aciduria UMP synthase Orotic acid Growth retardation... 

Webster DR, Becroft DMO, Van Gennip AH, Van Kuilenberg ABR Hereditary orotic aciduria and other disorders of pyrimidine metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, vol II, 8th Ed. New York McGraw-Hill, 2001 2663-2702. 

What is the biochemical basis of hereditary orotic aciduria ... 

Orotidine 5 -phosphate decarboxylase (ODCase, E. C. 4.1.1.23) catalyzes the decarboxylation of orotidine 5 -phosphate (OMP) to form uridine 5 -phos-phate in the sixth and final step of pyrimidine biosynthesis (Fig. 1) [1]. The discovery of ODCase in 1954 followed the identification, three years earlier, of orotic acid as the metabolic precursor of nucleic acids [2, 3]. ODCase is a distinct, monofunctional polypeptide in bacteria and fungi, whereas in mammals it combines with orotate phosphoribosyltransferase (OPRTase) to form the bifunctional enzyme UMP synthase. Human deficiencies in either OPRTase or ODCase activity result in an autosomal recessive disorder called hereditary orotic aciduria [4]. The disease is characterized by depleted levels of pyrimidine nucleotides in the blood and by the appearance of crystalline... 

The reduction in urinary excretion of both compounds following uridine therapy reflects the utilization of uridine for the formation of UMP by the salvage pathway. A similar phenomenon was observed in hereditary orotic aciduria following uridine replacement therapy which bypasses the congenital enzyme defect (Chapter 5). The reversal of 6-azauridine-induced orotic aciduria by hydroxyurea, methotrexate and cyclophosphamide [251] (i.e. by the drugs affecting the synthesis of DNA without any effect on orotic acid synthesis) suggests that the control of pyrimidine synthesis de novo is linked to DNA synthesis. 

Bll Becroft, D. M., Phillips, L. I. and Simmonds, A. Hereditary orotic aciduria long-term therapy with uridine and a trial of uracil. J. Pediatr., 75, 885-891 (1969)... 

Smith, L. H. and Gilmour, L. Determination of urinary carbamylaspartate and dihydroorotate in normal subjects and in patients with hereditary orotic aciduria. J. Lab. Clin. Med., 86, 1047-1051 (1975)... 

W29 Worthy, Th. E., Grobner, W. and Kelley, W. N. Hereditary orotic aciduria. Evidence for a structural gene mutation. Proc. Natl. Acad. Sci. USA, 71, 3031-3035 (1974)... 

The number of inherited defects of the pyrimidine metabolism described so far is small, compared to that of the purine metabolism. Combined deficiency of orotate phosphoribosyltransferase (OPRT) (EC 2.4.2.10) and orotidine 5 -monophosphate decarboxylase (ODC) (EC 4.1.1.23), designated as type I hereditary orotic aciduria, presents with characteristic clinical features such as hypochromic anemia with a megaloblastic bone marrow and crystalluria. Only six patients have been described and, as far as we know, new cases have not been discovered recently. ODC deficiency with similar clinical phenomena and leading to increased urinary excretion of orotate and orotidine has been detected in only one patient (1). A third defect, a deficiency of pyrimidine 5 -nucleotidase (Py-5NX (EC 3.1.3.5.) in erythrocytes, is associated with chronic hemolytic anemia and prominent basophylic stippling of the erythrocytes due to accumulated pyrimidine nucleotides. An increasing number of patients have been reported, their detection being facilitated by the typical phenomena. We do not know whether the urinary pyrimidine profile in this condition is abnormal. 

W.N. Kelley and L.H. Smildi Jr., Hereditary orotic aciduria, in "The Metabolic Basis of Inherited Disease, eds. J.B. Stanbury, J.B. Wijngaarden, D.S. Frederickson, McGraw-Hill Book Co., New York (1978), pp 1045-1071. 

Kelley and Beardmore, 1970 Beardmore, Cashman and Kelley, 1972). Similar values are seen with oxipurinol therapy. This represents a 7-10 fold increase over pretreatment values for orotic acid (<2.0 mg/24 hr) and orotidine (6.7 mg/24 hr) but is much less than the quantity excreted by patients with hereditary orotic aciduria who may excrete up to 1500 mg/24 hr. This pattern of excretion of pyrimidines is analogous to that observed during therapy with the pyrimidine analogue, 6-azauridine (Fallon, et al., 1961). 

The excretion of orotidine is also increased when allopurinol is administered to patients with the Lesch-Nyhan syndrome and hereditary orotic aciduria. Two children with the Lesch-Nyhan syndrome had base line orotidine levels of less than 2.0 mg/24 hr which increased to 18.1 and 24.3 mg/24 hr with treatment. Similar findings were seen in two patients with hereditary orotic aciduria who exhibited an increased excretion of orotidine from base line values of 34.8 and 21.3 mg/gm creatinine to 150 and 134 mg/gm creatinine. However, in neither genetic disorder was there a significant change in orotic acid excretion with allopurinol administration. 

Methylmalonic acidemia Propionic acidemia Carbamyl phosphate synthetase def. Lysinuric protein intolerance Hereditary orotic aciduria Wilson disease... 

Lysinuric protein intolerance Hereditary orotic aciduria Pyrimidine-5-nucleotidase def. Familial LCAT def. Wilson disease Acid lipase def. (Wolman disease) 3-Phosphoglycerate dehydrogenase deL Methylentetrahydrofolate reductase def. Methioninsynthase def. 

The broad spectrum of clinical presentation highlights the importance of particular steps in purine and pyrimidine metabolism to different cells and tissues and should have assisted in the development of appropriate treatment. Unfortunately, only three of the nineteen disorders described can be treated successfully hereditary orotic aciduria with life-long uridine, 2,8-di-hydroxyadenine lithiasis with allopurinol. ADA deficiency is treatable by bone marrow transplantation (BHT), or enzyme replacement with polyethylene glycol (PEG)-ADA, but the cost is prohibitive. Er/throcyte-encapsu-lated ADA is effective and less expensive. Oral ribose is reportedly beneficial in myoadenylate deaminase deficiency [1, 4] and also in adenylosucci-nase deficiency [1, 5]. PNP deficiency is also treatable by BMI. 

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