A 14-month-old boy is evaluated for failure to thrive and developmental delay. His mother reports that at 12 months he could barely lift his head and had difficulty sitting unsupported. The toddler has not started babbling or forming words. He is at the 10th percentile for height and 5th percentile for weight. Laboratory results are as follows:
Hemoglobin 8.6 g/dL Mean corpuscular volume 114 fL Reticulocytes 1% Ammonia, plasma 42 µg/dL normal: 40-80 µg/dL
Urine specimens contain large amounts of orotic acid crystals. Supplementation with which of the following substances would most likely benefit this patient?
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This patient likely has hereditary orotic aciduria, a rare autosomal recessive disorder of de novo pyrimidine synthesis that results in developmental delay (eg, low height/weight, absent developmental milestones), megaloblastic anemia (eg, elevated mean corpuscular volume, low reticulocyte count), and elevated urinary orotic acid levels. Increased urinary orotic acid may also be seen in ornithine transcarbamylase deficiency; however, patients with this condition classically have failure to thrive and hyperammonemic encephalopathy within the first few weeks of life (due to impaired urea synthesis).
Hereditary orotic aciduria occurs due to a defect in uridine 5'-monophosphate (UMP) synthase, a polypeptide containing 2 enzymatic domains (orotate phosphoribosyltransferase and OMP decarboxylase) that catalyze the final conversion of orotic acid to UMP. Impaired conversion of orotic acid to UMP results in the excretion of large amounts of orotic acid in the urine and the clinical features described above. Uridine supplementation can bypass this enzymatic defect and improve symptoms as uridine is converted to UMP via nucleoside kinases.
(Choice A) Ascorbic acid (vitamin C) is required for hydroxylation of proline and lysine residues in collagen synthesis; therefore, it plays an important role in connective tissue maintenance and wound healing.
(Choice B) Folate participates in single carbon transfer reactions, as in the de novo synthesis of purines and thymidine. Folate supplements will improve megaloblastic anemia resulting from folate deficiency but will not improve the anemia in orotic aciduria.
(Choice C) Guanine and adenine are purine bases present in DNA and RNA. Orotic aciduria is a defect in the synthesis of pyrimidine bases, so supplementation with purines would not affect orate synthesis.
(Choice D) Iron supplementation improves iron deficiency anemia, classically a microcytic hypochromic anemia.
(Choice E) Pyridoxine (vitamin B6) supplementation is indicated during treatment with isoniazid. Pyridoxine is a cofactor in transamination, deamination, decarboxylation, and condensation reactions.
Educational objective:
Orotic aciduria is a rare autosomal recessive disorder of de novo pyrimidine synthesis that occurs due to a defect in uridine 5'-monophosphate (UMP) synthase. Children typically present with developmental delay, megaloblastic anemia, and large amounts of urinary orotic acid. Uridine supplementation can improve symptoms as uridine is converted to UMP via nucleoside kinases.