UMPS – Hereditary Orotic Aciduria

Hereditary orotic aciduria is a rare autosomal recessive disorder of pyrimidine metabolism characterized by excessive urinary orotic acid, megaloblastic anemia, growth retardation, and neurodevelopmental deficits. The UMPS gene encodes a bifunctional enzyme, uridine monophosphate synthase, catalyzing the final steps of de novo pyrimidine biosynthesis. Pathogenic variants cause impaired orotate phosphoribosyltransferase and orotidine-5′-monophosphate decarboxylase activities.

Biallelic UMPS variants have been identified in multiple unrelated families. A Chinese pedigree harbored a homozygous c.517G>C (p.Val173Leu) variant in the proband with epilepsy and intellectual disability (PMID:35356460), and two additional reports described compound heterozygous missense alleles in Japanese and European patients presenting with anemia, growth delay, and orotic aciduria (PMID:9042911; PMID:25757096).

A cohort study of mild orotic aciduria identified 11 unrelated heterozygotes with normal hematologic parameters but isolated urinary metabolite elevations; none required treatment, although ascertainment bias for developmental symptoms may exist (PMID:28205048). This delineates that partial UMPS deficiency can manifest in heterozygous carriers without overt clinical consequences.

The variant spectrum includes missense changes (e.g., p.Val173Leu, p.Ile85Thr) and predicted loss-of-function alleles (e.g., p.Gly129Ter, p.Lys101fs), distributed across both enzymatic domains, underscoring the importance of autosomal recessive inheritance and allelic heterogeneity.

Functional assays in recombinant bacteria and insect cells for alleles p.Arg96Gly, p.Val109Gly, and p.Gly429Arg demonstrated markedly reduced enzyme activity correlating with urinary orotic acid accumulation (PMID:9042911). Complementation of ura3 and ura5 yeast mutants with a Dictyostelium discoideum UMPS cassette further confirms conserved catalytic function (PMID:8500761).

In summary, UMPS is definitively associated with hereditary orotic aciduria via autosomal recessive loss-of-function mutations. Standard diagnostic sequencing and urinary metabolite analysis enable early recognition and management with uridine supplementation. Key take-home: UMPS genetic testing is essential for accurate diagnosis of orotic aciduria and guides effective therapy.

References

• Frontiers in neurology • 2022 • Case Report: A Novel Missense Mutation c.517G>C in the UMPS Gene Associated With Mild Orotic Aciduria. PMID:35356460
• American journal of human genetics • 1997 • Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families. PMID:9042911
• Neuropediatrics • 2015 • Hereditary orotic aciduria with epilepsy and without megaloblastic anemia. PMID:25757096
• Journal of inherited metabolic disease • 2017 • Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences. PMID:28205048
• Gene • 1993 • Construction of a UMP synthase expression cassette from Dictyostelium discoideum. PMID:8500761

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