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Wortmann, S.B. ; Chen, M.A.* ; Colombo, R.* ; Pontoglio, A.* ; Alhaddad, B.* ; Botto, L.D.* ; Yuzyuk, T.* ; Coughlin, C.R.* ; Descartes, M.* ; Grűnewald, 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.*

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

J. Inherit. Metab. Dis. 40, 423-431 (2017)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Background: 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Megaloblastic-anemia; Molecular-cloning; Synthase Gene; Uridine; Decarboxylase; Fibroblasts
ISSN (print) / ISBN 0141-8955
e-ISSN 1573-2665
Zeitschrift Journal of Inherited Metabolic Disease
Quellenangaben Band: 40, Heft: 3, Seiten: 423-431 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Dordrecht
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)