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A 4-year-old girl presented to the clinic with Megaloblastic anemia and failure to thrive. History revealed that the child was born normally. The red blood cell count was 2.55 millions/cmm and hemoglobin was 6g/dl. He was given antibiotics and transfusions. Despite that the anemia worsened. There was no response following treatment with B12, Folic acid, or pyridoxine.

A prominent feature of the child’s urine was a crystalline sediment, which was found to be orotic acid. Orotic acid in amounts as high as 1500 mg (9.6 mmol) was excreted daily (Normal 1.4 mg/day, 9 μmol). Enzyme measurements of white blood cells revealed a deficiency of the pyrimidine biosynthesis enzyme orotate phosphoribosyltransferase and abnormally high activity of enzyme Aspartate Transcarbamoylase.

What is the  nature of the disease?

How can this be treated?


Case Discussion

The child is suffering from Orotic aciduria.

Orotic aciduria

Basic concept

Orotic aciduria refers to an excessive excretion of Orotic acid in urine.This is a disorder of pathway of pyrimidine biosynthesis.

Biochemical Defect

Orotic aciduria is a rare Autosomal recessive disorder. The usual form of hereditary Orotic aciduria is the build up of Orotic acid due to the deficiency in one or both of enzymes that convert it to UMP. Either orotate phosphoribosy ltransferase and orotidylate decarboxylase both are defective, or the decarboxylase alone is defective. It can also arise secondary to blockage of the urea cycle, particularly ornithine Trans carbamoylase deficiency.

Pathway of Pyrimidine Biosynthesis


 Figure-showing the steps of de novo pyrimidine nucleotide biosynthesis

The first step in de novo pyrimidine biosynthesis is the synthesis of Carbamoyl phosphate from bicarbonate and glutamine in a multistep process, requiring the cleavage of two molecules of ATP. This reaction is catalyzed by Carbamoyl phosphate synthetase -II (CPS-II ). Carbamoyl phosphate synthetase-II  primarily uses glutamine as a source of ammonia.

Carbamoyl phosphate reacts with aspartate to form Carbamoyl aspartate in a reaction catalyzed by aspartate Transcarbamoylase. Carbamoyl aspartate cyclizes to form Dihydro orotate, which then gets oxidized by  Dihydro orotate dehydrogenase in the presence of NAD+  to form orotate. At this stage, orotate couples to ribose, in the form of 5-phosphoribosyl-1-pyrophosphate (PRPP), a form of ribose activated to accept nucleotide bases. Orotate reacts with PRPP to form orotidylate (Orotate mono phosphate), a pyrimidine nucleotide. This reaction is driven by the hydrolysis of pyrophosphate. The enzyme that catalyzes this addition, pyrimidine phosphoribosyl transferase, is homologous to a number of other phosphoribosyl transferases that add different groups to PRPP to form the other nucleotides. 

Orotidylate is then decarboxylated to form uridylate (UMP), a major pyrimidine nucleotide that is a precursor to RNA. This reaction is catalyzed by orotidylate decarboxylase. This enzyme is one of the most proficient enzymes known. In its absence, decarboxylation is extremely slow and is estimated to take place once every 78 million years; with the enzyme present, it takes place approximately once per second, a rate enhancement of many folds !

UMP is the parent nucleotide; the other pyrimidine nucleotides are formed from UMP.

Clinical manifestations

This disorder usually appears in the first year of life and is characterized by growth failure, developmental retardation, megaloblastic anemia, and increased urinary excretion of Orotic acid.

UMP, The end product of this pathway, 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. Specially, the lack of CTP inhibition allows Aspartate Transcarbamoylase to remain highly active. This results in more and more production of Orotic acid which gets accumulated and is excreted in urine excessively.

Lack of CTP, TMP, and UTP leads to a decreased nucleic acid synthesis and decreased erythrocyte formation resulting in Megaloblastic anemia. 

Physical and mental retardation are frequently present. The anemia is refractory to vitamin B12 or folic acid.

Laboratory Diagnosis

The diagnosis of this disorder is suggested by the presence of severe Megaloblastic anemia with normal serum B12 and Folate levels and no evidence of TC-II deficiency ( Transcobalamine- II).A presumptive diagnosis is made by finding increased urinary orotic acid. Confirmation of the diagnosis, however, requireassay of the Transferase and decarboxylase enzymes in the patient’s erythrocytes


Uridine treatment is effective because Uridine can easily be converted into UMP by omnipresent tissue kinase, thus allowing UTP, CTP, and TMP to be synthesized and feedback inhibit further Orotic acid production.

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