Orotic Megaloblastic anemia

Answen B. Accumulation of orotic acid indicates megaloblastic anemia arises since pyrimidines are required for DNA synthesis. 

Low activities of orotidine phosphate decarboxylase and orotate phosphoribosyltransferase result in abnormal growth, megaloblastic anemia and the excretion of large amounts of orotate in the urine. 

Low activities of orotidine phosphate decarboxylase and (usually) orotate phosphoribosyltransferase are associated with a genetic disease in children that is characterized by abnormal growth, megaloblastic anemia, and the excretion of large amounts of orotate. When affected children are fed a pyrimidine nucleoside, usually uridine, the anemia decreases and the excretion of orotate diminishes. A likely explanation for the improvement is that the ingested uridine is phosphorylated to UMP, which is then converted to other pyrimidine nucleotides so that nucleic acid and protein synthesis can resume. In addition, the increased intracellular concentrations of pyrimidine nucleotides inhibit carbamoyl phosphate synthase, the first enzyme in the. naibwav of aro-tate synthesis. 

A 4-year-old girl presents in the clinic with megaloblastic anemia and failure to thrive. Blood chemistries reveal orotic aciduria. Enzyme measurements of white blood cells reveal a deficiency of the pyrimidine biosynthesis enzyme orotate phosphoribosyltransferase and abnormally high activity of the enzyme aspartate transcarbamoylase. Which one of the following treatments will reverse all symptoms if carried out chronically ... 

The answer is e. (Murray, pp 375-401. Scriver, pp 2663-2704. Sack, pp 121-138. Wilson, pp 287—320.) Orotic aciduria is the buildup of orotic acid due to a deficiency in one or both of the enzymes that convert it to UMP Either orotate phosphoribosyltransferase and orotidylate decarboxylase are both defective, or the decarboxylase alone is defective. UMP is the precursor of UTP, CTP, and TMP All of these end products normally act in some way to feedback-inhibit the initial reactions of pyrimidine synthesis. Specifically, the lack of CTP inhibition allows aspartate transcarbamoylase to remain highly active and ultimately results in a buildup of orotic acid and the resultant orotic aciduria. The lack of CTP, TMP, and UTP leads to a decreased erythrocyte formation and megaloblastic anemia. Uridine treatment is effective because uridine can easily be converted to UMP by omnipresent tissue kinases, thus allowing UTP, CTP, and TMP to be synthesized and feedback-inhibit further orotic acid production. 

Ororid i -5 -phosphate pyrophosphorylase (EC 2.4.2.10) and orotidme-5 -phosphate decarboxylase (EC 4.1.1.23). Abnormally high urinary orotic add. Severe megaloblastic anemia. Marked retardation of growth and development, and slight mental retardation. [A gross defidency of 2 enzymes of pyrimidine biosynthesis]... 

Apparently, both the granulopoietic and the erythropoietic lineage participated in the megaloblastic proliferation. Thus, the most salient hematological feature was a hyperchromic megaloblastic anemia. The only other abnormality was found in the urine, where large amounts of pyrimidine bases, later demonstrated to be orotic acid, were excreted. Such observations suggest either a block in orotic acid use for further biosynthesis of pyrimidine and nucleic acid, or interference with renal orotic acid excretion. 

The accumulation in blood and the excessive urinary excretion of orotic acid are postulated to result from the absence of either decarboxylase or the pyrophos-phorylase. These enzyme activities could not be directly assayed in the patient s tissues, but assays in the parents and two of the siblings indicated that the activities of both decarboxylase and phosphorylase were defective. In the patients described, the orotic aciduria and the megaloblastic anemia that it causes could be relieved by injecting nucleotides (cytidylic and uridylic acid). And in addition to its therapeutic significance, this observation also provides some invaluable information on the functioning of the pyrimidine metabolic pathway in vivo. 

The resultant clinical state is characterized by failure of growth and development, megaloblastic anemia, and the increased urinary excretion of orotic acid (Types I and II) and orotidine (Type II). 

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. 

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