Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences

Abstract

BackgroundElevated urinary excretion of orotic acid is associated with treatable disorders of the urea cycle and pyrimidine metabolism. Establishing the correct and timely diagnosis in a patient with orotic aciduria is key to effective treatment. Uridine monophosphate synthase is involved in de novo pyrimidine synthesis. Uridine monophosphate synthase deficiency (or hereditary orotic aciduria), due to biallelic mutations in UMPS, is a rare condition presenting with megaloblastic anemia in the first months of life. If not treated with the pyrimidine precursor uridine, neutropenia, failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue.Methods and resultsWe identified mild and isolated orotic aciduria in 11 unrelated individuals with diverse clinical signs and symptoms, the most common denominator being intellectual disability/developmental delay. Of note, none had blood count abnormalities, relevant hyperammonemia or altered plasma amino acid profile. All individuals were found to have heterozygous alterations in UMPS. Four of these variants were predicted to be null alleles with complete loss of function. The remaining variants were missense changes and predicted to be damaging to the normal encoded protein. Interestingly, family screening revealed heterozygous UMPS variants in combination with mild orotic aciduria in 19 clinically asymptomatic family members.ConclusionsWe therefore conclude that heterozygous UMPS-mutations can lead to mild and isolated orotic aciduria without clinical consequence. Partial UMPS-deficiency should be included in the differential diagnosis of mild orotic aciduria. The discovery of heterozygotes manifesting clinical symptoms such as hypotonia and developmental delay are likely due to ascertainment bias.

Pathophysiological Role of Purines and Pyrimidines in Neurodevelopment: Unveiling New Pharmacological Approaches to Congenital Brain Diseases

“…In the second step, orotidine decarboxylase (ODC) generates UMP. Very high orotate levels (up to 400-fold compared to control subjects) are found in urine and plasma of patients suffering from the disease (Wortmann et al, 2017 ). Children with UMPS deficiency have a strong pyrimidine starvation and, if untreated, can develop growth retardation, intellectual disability, and epilepsy.…”

The role of orotic acid measurement in routine newborn screening for urea cycle disorders

“…For orotic acid, we aimed at a cutoff based on our other mass spectroscopy analytes flagging the highest 0.03 centile (orotic acid greater than 4.86 μmol/L) with a reduction to a safety zone of 4 μmol/L (0.05 centile) as our final cutoff (Table 1). The combination of citrulline with orotic acid is expected to detect the same flagged rate (0.03‐0.04%) as for other metabolic disorders (Table 3) while avoiding detecting mild persistent orotic aciduria without clinical consequences 21 …”

“…The combination of citrulline with orotic acid is expected to detect the same flagged rate (0.03-0.04%) as for other metabolic disorders (Table 3) while avoiding detecting mild persistent orotic aciduria without clinical consequences. 21 Reducing the cutoff of orotic acid to 2.4 μmol/L would have identified three out of the four missed OTCD casesbut would have resulted in an enormous number of false positives and therefore was not considered to be appropriate.…”

Case Report: A Novel Missense Mutation c.517G>C in the UMPS Gene Associated With Mild Orotic Aciduria

“…Hereditary orotic aciduria (HOA) (OMIM # 258900 ) is a rare genetic disorder of pyrimidine metabolism characterized by early onset of megaloblastic anemia, global developmental delay, and failure to thrive, which is associated with massive urinary overexcretion of orotic acid (sometimes with orotic acid crystalluria) ( 1 ). Patients without megaloblastic anemia, but with additional manifestations such as epilepsy, have also been reported ( 2 ).…”