title: Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Mullner Hauptstrasse 48, 5020, Salzburg, Austria. s.wortmann-hagemann@salk.at.|Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany. s.wortmann-hagemann@salk.at.|Institute of Human Genetics, Technical University Munich, Munich, Germany. s.wortmann-hagemann@salk.at.
authors.forename: Saskia B
authors.initials: SB
authors.lastname: Wortmann
authors.affiliation: Prevention Genetics, Marshfield, WI, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Chen
authors.affiliation: Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Colombo
authors.affiliation: Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pontoglio
authors.affiliation: Institute of Human Genetics, Technical University Munich, Munich, Germany.
authors.forename: Bader
authors.initials: B
authors.lastname: Alhaddad
authors.affiliation: Department of Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Lorenzo D
authors.initials: LD
authors.lastname: Botto
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.|ARUP Laboratories, Salt Lake City, UT, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Yuzyuk
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Coughlin
authors.affiliation: Departments of Genetics and Pediatrics, University of Alabama School of Medicine, Birmingham, AL, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Descartes
authors.affiliation: Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, and UCL Institute of Child Health, London, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grűnewald
authors.affiliation: CHUS Genetic Services, University of Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.affiliation: Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, UK.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.affiliation: Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Pitt
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Potente
authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: Rodenburg
authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A J
authors.initials: LA
authors.lastname: Kluijtmans
authors.affiliation: Prevention Genetics, Marshfield, WI, USA.
authors.forename: Srirangan
authors.initials: S
authors.lastname: Sampath
authors.affiliation: Princess Margaret Cancer Centre, and Departments of Biochemistry, Medical Biophysics, and Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.affiliation: Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Tiller
mesh_terms: D000749:Anemia, Megaloblastic / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism; D008297:Male; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009962:Orotate Phosphoribosyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009963:Orotic Acid / Q000378:metabolism; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism; D056806:Urea Cycle Disorders, Inborn / Q000235:genetics / Q000378:metabolism; D014529:Uridine / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D011743:Pyrimidines; D009963:Orotic Acid; C027157:uridine 5'-monophosphate synthase; D009962:Orotate Phosphoribosyltransferase; D009964:Orotidine-5'-Phosphate Decarboxylase; C030986:pyrimidine; D014529:Uridine