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J Inherit Metab Dis ; 40(3): 423-431, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28205048

RESUMEN

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.


Asunto(s)
Complejos Multienzimáticos/genética , Complejos Multienzimáticos/metabolismo , Orotato Fosforribosiltransferasa/deficiencia , Orotidina-5'-Fosfato Descarboxilasa/deficiencia , Errores Innatos del Metabolismo de la Purina-Pirimidina/metabolismo , Anemia Megaloblástica/genética , Anemia Megaloblástica/metabolismo , Niño , Preescolar , Femenino , Heterocigoto , Humanos , Lactante , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Masculino , Mutación/genética , Orotato Fosforribosiltransferasa/genética , Orotato Fosforribosiltransferasa/metabolismo , Ácido Orótico/metabolismo , Orotidina-5'-Fosfato Descarboxilasa/genética , Orotidina-5'-Fosfato Descarboxilasa/metabolismo , Errores Innatos del Metabolismo de la Purina-Pirimidina/genética , Pirimidinas/metabolismo , Trastornos Innatos del Ciclo de la Urea/genética , Trastornos Innatos del Ciclo de la Urea/metabolismo , Uridina/metabolismo
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