Megaloblastic anemia in the presence of normal Folic acid and Vitamin B12- Case discussion

Case details

A 6-month-old infant is seen by the pediatrician for developmental delay. Blood work shows megaloblastic anemia, although measurements of B12 and folate are in the high normal range. Urinalysis demonstrates, upon standing, the formation of a crystalline substance. Supplementation of the child’s diet with uridine reversed virtually all of the clinical problems. The crystalline substance was most likely composed of which of the following?

A. Uracil

B. Thymine

C. Orotate

D. Aspartate

E. Cytosine

Answer- The correct answer is C-Orotate.

The child seems to be suffering from Hereditary orotic aciduria. Orotic aciduria refers to an excessive excretion of orotic acid in urine.

It is a rare Autosomal recessive disorder. The usual form of hereditary orotic aciduria is the buildup of Orotic acid due to the deficiency in one or both of enzymes that convert it to UMP. Either orotate phosphoribosyl transferase and orotidylate decarboxylase both are defective, or the decarboxylase alone is defective (figure). It can also arise secondary to blockage of the urea cycle, particularly ornithine Transcarbamoylase deficiency.

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/UTP  inhibition allows Aspartate Transcarbamoylase to remain highly active (figure).

Steps of pyrimidine nucleotide biosynthesis

Figure-Steps of pyrimidine biosynthesis

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.

Uridine supplementation leads to its conversion to UMP, UDP and UTP which causes feed back inhibition of initial reactions of pyrimidine nucleotide biosynthesis. This reduces orotic formation and relief of symptoms.

The crystals are made of orotate, as that is the compound that is accumulating. Uracil, thymine, and cytosine would not be synthesized in a patient with this disorder. Aspartate is very soluble and would not form crystals if it were to accumulate.


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