Abstract | BACKGROUND: 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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Authors | Saskia B Wortmann, Margaret A Chen, Roberto Colombo, Alessandro Pontoglio, Bader Alhaddad, Lorenzo D Botto, Tatiana Yuzyuk, Curtis R Coughlin, Maria Descartes, Stephanie Grűnewald, Bruno Maranda, Philippa B Mills, James Pitt, Catherine Potente, Richard Rodenburg, Leo A J Kluijtmans, Srirangan Sampath, Emil F Pai, Ron A Wevers, George E Tiller, additional individual contributors |
Journal | Journal of inherited metabolic disease
(J Inherit Metab Dis)
Vol. 40
Issue 3
Pg. 423-431
(05 2017)
ISSN: 1573-2665 [Electronic] United States |
PMID | 28205048
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Multienzyme Complexes
- Pyrimidines
- Orotic Acid
- uridine 5'-monophosphate synthase
- Orotate Phosphoribosyltransferase
- Orotidine-5'-Phosphate Decarboxylase
- pyrimidine
- Uridine
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Topics |
- Anemia, Megaloblastic
(genetics, metabolism)
- Child
- Child, Preschool
- Female
- Heterozygote
- Humans
- Infant
- Intellectual Disability
(genetics, metabolism)
- Male
- Multienzyme Complexes
(genetics, metabolism)
- Mutation
(genetics)
- Orotate Phosphoribosyltransferase
(deficiency, genetics, metabolism)
- Orotic Acid
(metabolism)
- Orotidine-5'-Phosphate Decarboxylase
(deficiency, genetics, metabolism)
- Purine-Pyrimidine Metabolism, Inborn Errors
(genetics, metabolism)
- Pyrimidines
(metabolism)
- Urea Cycle Disorders, Inborn
(genetics, metabolism)
- Uridine
(metabolism)
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