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dc.contributor.authorWortmann, SB
dc.contributor.authorChen, MA
dc.contributor.authorColombo, R
dc.contributor.authorPontoglio, A
dc.contributor.authorAlhaddad, B
dc.contributor.authorBotto, LD
dc.contributor.authorYuzyuk, T
dc.contributor.authorCoughlin, CR
dc.contributor.authorDescartes, M
dc.contributor.authorGrunewald, S
dc.contributor.authorMaranda, B
dc.contributor.authorMills, PB
dc.contributor.authorPitt, J
dc.contributor.authorPotente, C
dc.contributor.authorRodenburg, R
dc.contributor.authorKluijtmans, LAJ
dc.contributor.authorSampath, S
dc.contributor.authorPai, EF
dc.contributor.authorWevers, RA
dc.contributor.authorTiller, GE
dc.date.accessioned2020-12-22T05:29:53Z
dc.date.available2020-12-22T05:29:53Z
dc.date.issued2017-05-01
dc.identifierpii: 10.1007/s10545-017-0015-9
dc.identifier.citationWortmann, S. B., Chen, M. A., Colombo, R., Pontoglio, A., Alhaddad, B., Botto, L. D., Yuzyuk, T., Coughlin, C. R., Descartes, M., Grunewald, S., Maranda, B., Mills, P. B., Pitt, J., Potente, C., Rodenburg, R., Kluijtmans, L. A. J., Sampath, S., Pai, E. F., Wevers, R. A. & Tiller, G. E. (2017). Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences. JOURNAL OF INHERITED METABOLIC DISEASE, 40 (3), pp.423-431. https://doi.org/10.1007/s10545-017-0015-9.
dc.identifier.issn0141-8955
dc.identifier.urihttp://hdl.handle.net/11343/258302
dc.description.abstractBACKGROUND: Elevated 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 RESULTS: We 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. CONCLUSIONS: We 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.
dc.languageEnglish
dc.publisherSPRINGER
dc.titleMild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences
dc.typeJournal Article
dc.identifier.doi10.1007/s10545-017-0015-9
melbourne.affiliation.departmentPaediatrics (RCH)
melbourne.source.titleJournal of Inherited Metabolic Disease
melbourne.source.volume40
melbourne.source.issue3
melbourne.source.pages423-431
dc.rights.licenseCC BY
melbourne.elementsid1190900
melbourne.contributor.authorWhite, Susan
melbourne.contributor.authorPitt, James
dc.identifier.eissn1573-2665
melbourne.accessrightsOpen Access


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