Abstract
Hereditary orotic aciduria (HOA) is a very rare inborn error of pyrimidine metabolism. It results from a defect of the uridine-5-monophosphate synthase (UMPS) gene. To date, only about twenty patients have been described. We report a case of HOA with a novel variant in the UMPS gene. A 17-year-old Emirati girl was born to first-cousin parents. During the first year, she had recurrent, severe infections including disseminated varicella. After evaluation for immunodeficiency, an impression of immunodeficiency of unknown etiology was presumed. Frequent episodes of pancytopenia were also noted. Bone marrow biopsy showed trilineage megaloblastoid maturation with dysplastic changes that were refractory to hematinic therapy. Also, she was noted to have failure to thrive, developmental delay and epilepsy. She was referred to the Genetics clinic where whole-exome sequencing (WES) was done and showed a novel homozygous variant in the UMPS gene confirming a diagnosis of HOA. She was started on uridine triacetate after which she showed clinical, hematologic and biochemical improvement. Although extremely rare, hereditary orotic aciduria should be suspected in any child with megaloblastic bone marrow, immunodeficiency or when developmental delay and anemia coexist.
Highlights
Hereditary orotic aciduria (HOA) (OMIM #258900) is a rare inborn error of pyrimidine metabolism with autosomal recessive inheritance [2]
uridine-5-monophosphate synthase (UMPS) defects lead to the accumulation of orotate (OA) and/or of orotidine monophosphate (OMP), which will eventually be excreted in the urine [8]
She was born extremely premature at 28 weeks of gestation and was admitted to the newborn intensive care unit (NICU), where she stayed for 100 days
Summary
Hereditary orotic aciduria (HOA) (OMIM #258900) is a rare inborn error of pyrimidine metabolism with autosomal recessive inheritance [2]. It is the only known enzyme deficiency of the pyrimidine biosyn thetic pathway, resulting from a deficiency in one or both of the activ ities of the bifunctional enzyme uridine-5-monophosphate synthase (UMPS) (EC 4.1.1.23) encoded by the UMPS gene. UMPS defects lead to the accumulation of orotate (OA) and/or of orotidine monophosphate (OMP), which will eventually be excreted in the urine [8]. The hallmarks of the disease are a megaloblastic bone marrow that is refractory to hematinic therapy, accompanied by a markedly increased excretion of orotic acid in the urine. Only one case described an associated epileptic disorder [4]
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