Orotic aciduria
Orotic aciduria is a rare genetic disorder that typically manifests in early childhood and is characterized by megaloblastic anemia and excessive urinary excretion of orotic acid. This condition arises from a deficiency in uridine monophosphate (UMP) synthase, an enzyme crucial for nucleotide synthesis, which is vital for cell replication, especially in the production of red blood cells. Without adequate UMP synthase activity, affected individuals experience anemia and developmental delays, highlighting the importance of early diagnosis and treatment.
Genetically, orotic aciduria is inherited in an autosomal recessive pattern, and it affects individuals of all genders equally, with mutations found on chromosome 3. Symptoms can include poor growth and cognitive delays, prompting urgent medical evaluation for infants exhibiting signs of anemia or unusual crystals in urine. The condition is diagnosed through blood tests, urinalysis, and enzyme activity assessment.
Treatment with uridine, which can bypass the defective enzyme pathway, has been shown to reverse anemia and support normal growth and development, although it requires lifelong management. The rarity of this condition means that preventive measures and prenatal diagnostics are typically limited to families with a history of the disorder. Overall, with appropriate management, many individuals with orotic aciduria can lead fulfilling lives.
Orotic aciduria
ALSO KNOWN AS: Hereditary orotic aciduria; deficiency of uridine monophosphate synthase
DEFINITION Orotic aciduria, a rare genetic defect that appears early in life, is characterized by megaloblastic anemia and urinary excretion of high levels of orotic acid. Unrecognized, it retards physical and intellectual development. Treatment with uridine reverses the anemia and reduces orotic acid excretion; early treatment permits normal growth and development.
Risk Factors
The disease exhibits a familial association and is due to a deleterious mutation in the gene for uridine monophosphate (UMP) synthase. While the condition is rare (only fifteen cases have been documented), the condition is widely dispersed geographically and ethnically. It affects boys and girls equally.
Etiology and Genetics
Orotic aciduria is an autosomal recessive condition involving a mutation in the gene for UMP synthase, which is located on the long arm of chromosome 3 in the region 3q13. Four mutations have been identified that result in an inactive or unstable enzyme. They are unlikely to be the only mutations that give rise to the condition.
UMP synthase is an unusual in having two different activities: orotate phosphoribosyltransferase (OPRT) converts orotic acid to orotidine monophosphate (OMP) and OMP decarboxylase (ODC) converts OMP to UMP. These activities are two steps in the synthesis of nucleotides, which are constituents of DNA and RNA. Deleterious mutations produce an enzyme defective in both activities (Type I) or just the ODC activity (Type II). In either case, the cells of the affected individual cannot make pyrimidines from scratch and cell is impaired. The fact that megaloblastic anemia is one of the early symptoms is a function of the high degree of cell replication that is necessary for making new red blood cells in the bone marrow. Failure to thrive and developmental retardation also follow from the failure of cells to replicate. The excretion of orotic acid is due to the fact that OPRT is the only way to metabolize this compound, which consequently builds up in tissues, spills into the blood, and is cleared by the kidney into urine. Treatment with uridine, which can be converted directly to UMP, provides an alternate pathway for pyrimidine synthesis, rectifying the anemia and developmental retardation. The reduction in orotic acid excretion reflects that a plentiful supply of pyrimidine nucleotides signals that orotic acid production can be minimized. The fact that the condition is observed postnatally indicates that maternal uridine provides sufficient pyrimidines for normal development in utero.
A deficiency of UMP synthase has also been observed in dairy cattle. In this case, it results in embryonic mortality around day forty of gestation, indicating that maternal uridine is not sufficient or is poorly transported across the placenta in this species. The mutation responsible has been identified. Heterozygotes have half the normal level of the enzyme in red blood cells and other tissues. In cattle, heterozygotes can be distinguished from normal on the basis of red blood cell enzyme levels, but in humans the variability in normal values makes this unreliable.
Symptoms
Orotic aciduria in humans presents as a megaloblastic anemia within weeks or months of birth. If untreated, it will cause failure to thrive and retardation in growth and development. In addition, urinary excretion of elevated orotic acid is observed, sometimes leading to crystal formation. Any infant who is anemic, growing poorly, slow in developing, and/or with crystals in its urine, should be brought for medical attention immediately.
Screening and Diagnosis
A hematocrit will show the anemia. Peripheral blood smears and bone marrow examination will indicate the megaloblastic anemia. If it does not respond to iron, folic acid, or vitamin B12 , orotic aciduria may be suspected. Analysis of the urine and any urinary crystals for orotic acid will confirm the suspicions. Analysis of red blood cells for very low UMP synthase activity will establish the diagnosis.
Treatment and Therapy
Treatment with uridine will eliminate the anemia, permit normal development, and reduce orotic acid excretion. In most patients, uridine administered orally has been effective, although one patient required intramuscular injections. The doses of uridine required to control the condition have been remarkably variable between individuals, although doses between 100 and 200 mg/kg/day have generally been effective. The treatment is expected to be lifelong, and doses have needed to be adjusted in some patients over time. Nevertheless, many treated patients have led normal lives and live into their late thirties.
Prevention and Outcomes
While prenatal diagnosis for the disease would be possible, the condition is so rare that this is not warranted except in cases where a sibling has been affected. Early neonatal diagnosis is essential to prevent any permanent developmental deficits.
Bibliography
Devlin, Thomas M. Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2005.
Fernandes, John, Jean-Marie Saudubray, Georges van den Berghe, and John H. Walter. Inborn Metabolic Diseases.4th ed. Berlin: Springer, 2006.
Lewis, Ricki. Human Genetics. 8th ed. New York: McGraw-Hill, 2007.
Staretz-Chacham, Orma, et al. "Heredity Orotic Aciduria Identified by Newborn Screening." Frontiers in Genetics, vol. 14, 14 Mar. 2023, doi.org/10.3389%2Ffgene.2023.1135267. Accessed 9 Sept. 2024.