Hereditary Orotic Aciduria

Disease Overview

Hereditary orotic aciduria is an extremely rare genetic disorder. When untreated, affected infants can develop a blood (hematologic) disorder called megaloblastic anemia as well as difficulty growing and gaining weight (failure to thrive), susceptibility to infection and orotic acid crystals in the urine (crystalluria). Neurological development may also be impaired, although this is less commonly observed, especially now that effective treatment is available.

Because so few people have been identified with this disorder, much about hereditary orotic aciduria is not fully understood. The disorder is caused by changes (variants) in the UMPS gene. In 2015, the U.S. Food and Drug Administration (FDA) approved a treatment called uridine triacetate (Xuriden) for this disorder.

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Synonyms

• orotidylic decarboxylase deficiency
• uridine monophosphate synthetase deficiency
• orotic aciduria type 1
• OA type 1
• orotidylic pyrophosphorylase and orotidlyic decarboxylase deficiency
• UMPS deficiency
• uridine monophosphate synthase deficiency
• OPRT and ODC deficiency
• UMP synthase deficiency

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Signs & Symptoms

People with hereditary orotic aciduria may have the following signs and symptoms:

• Megaloblastic anemia, a condition in which the bone marrow produces unusually large, structurally abnormal, immature red blood cells (megaloblasts)
  • Usually becomes apparent within the first few months of life
• Neurological problems including delays in reaching developmental milestones (developmental delays)
• Intellectual disability, usually mild
• Seizures (epilepsy)
• Difficulties gaining weight and growing (failure to thrive) in infants and younger children
  • As children grow older height and weight appear to be in the normal range
• Cloudy urine because of orotic acid crystals (crystalluria)
• Obstructive uropathy, a condition where blockage in the urinary tract prevents normal urine flow that can be caused by orotic acid crystals

This blockage can cause urine to back up, lead to blood in the urine (hematuria) and result in other complications also caused by orotic acid crystals. Other symptoms have been reported in one or two individuals, but researchers are not sure if they are features of the disorder or if they occurred for other reasons or were coincidental findings. These symptoms include diarrhea, congenital malformations, inflammation of the mouth and lips (stomatitis) and misalignment of the eyes (strabismus). Some affected infants had congenital heart disease including septal defects. Septal defects are abnormalities in the walls (septum) that separate the lower chambers of the heart (ventricles) or the upper chambers of the heart (atria).

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Causes

Hereditary orotic aciduria is caused by changes (variants) in the uridine monophosphate synthetase (UMPS) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.

The UMPS gene produces (encodes) a specialized protein (enzyme) called uridine 5’-monophosphate synthase. This enzyme is a bifunctional, which means it has the capacity to cause (catalyze) two consecutive metabolic reactions. In this case, it catalyzes the last two steps of the pyrimidine biosynthesis pathway. A pathway is a series of biochemical processes in which certain substances are broken down or created. This pathway creates a type of pyrimidine called uridine monophosphate. Pyrimidines are compounds found in deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and certain molecules within the body. One of these final two steps is to convert orotic acid into another chemical substance. Because of variants in the UMPS gene, affected individuals have very low levels of the enzyme needed to break down orotic acid. This causes orotic acid to build up in the body. Some of the excess orotic acid is passed through the urine. In addition to being broken down in the pyrimidine biosynthesis pathway, orotic acid is also thought to improve the metabolism of folic acid and vitamin B12, and may play a role in gene transcription, which is the process by which genetic information is copied from DNA to RNA to create a useful product like a specific protein.

There are reports in the medical literature of individuals who have variants in the UMPS gene but have only developed very mild symptoms that did not cause any significant problems. The exact manner by which orotic acid buildup and uridine monophosphate synthase deficiency ultimately lead to the signs and symptoms associated with this disorder is not completely understood yet.

Inheritance

Hereditary orotic aciduria follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

Hereditary orotic aciduria is an extremely rare disorder that affects both males and females. Only about 20 individuals with this disorder have been reported in the medical literature. The birth prevalence, which is the number of babies born with a disorder compared to the total number of live births, is estimated to be less than 1 in 1,000,000 live births. Because rare diseases often go misdiagnosed or undiagnosed, determining their true frequency in the general population is extremely difficult.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of hereditary orotic aciduria. Comparisons may be useful for a differential diagnosis.

Urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood. People with urea cycle disorders can also have elevated levels of orotic aid in the urine.

Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body.

Elevated levels or orotic acid in the urine have also been seen in lysinuric protein intolerance, Rett syndrome, certain forms of liver disease, certain forms of cancer and secondary to the use of certain medications. Several other conditions can cause megaloblastic anemia including various forms of leukemia, Lesch-Nyhan syndrome and deficiencies in cobalamin (vitamin B12) or folate (vitamin B9).

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Diagnosis

A diagnosis of hereditary orotic aciduria is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and examination of the urine.

Examination of the urine (urinalysis) can reveal elevated levels of orotic acid. Other conditions, such as the urea cycle disorders, can also cause elevated levels of orotic acid. However, these disorders also cause elevated levels of ammonia in the blood, while hereditary orotic aciduria does not.

For most people, the diagnosis is confirmed through molecular genetic testing that detects variants in the UMPS gene known to cause the disorder.

Expanded newborn screening, such as tandem mass spectrometry panels in some countries like Israel, may detect elevated orotic acid at birth and lead to earlier diagnosis in asymptomatic newborns. However, in the U.S. as of August 2025, newborn screening does not currently test for this condition.

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Standard Therapies

Treatment
In 2015, the U.S. Food and Drug Administration (FDA) approved a treatment called uridine triacetate (Xuriden) for hereditary orotic aciduria. This medication restores the chemical compound called uridine monophosphate (sometimes just called uridine). Because of the underlying genetic abnormality, affected individuals cannot create (synthesize) enough uridine monophosphate on their own. Clinical trials investigating this medication showed improvement in anemia and disappearance of megaloblastosis and a decrease in orotic acid levels in the urine. Affected individuals also showed improvement in or remained stable in gaining weight or growth. Researchers think that affected individuals must remain on this treatment throughout their lives to ensure orotic acid levels remain decreased.

Although only a small number of people have been diagnosed with hereditary orotic aciduria, some affected individuals who were treated have gone to school, got married, have had children, and have lived a relatively unaffected lifestyle. Researchers do not know whether hereditary orotic aciduria can cause long-term complications.

Any additional treatments are directed toward the specific symptoms that are present in each individual.

Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS

Nyhan WL, Barshop BA, Aida L Al-Aqeel. Atlas of Inherited Metabolic Diseases, 3rd Edition. Hodder Arnold Publishers. 2012.

Scriver CR, Beaudet AL, Sly WS, et al, Eds. The Metabolic Molecular Basis of Inherited Disease, 7th ed. McGraw-Hill Companies. New York, NY; 1995:1809-1823.

JOURNAL ARTICLES

Staretz-Chacham O, Damseh NS, Daas S, et al. Hereditary orotic aciduria identified by newborn screening. Front Genet. 2023;14:1135267. Published 2023 Mar 14. doi:10.3389/fgene.2023.1135267

Wortmann SB, Chen MA, Colombo R, et al. Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences. J Inherit Metab Dis. 2017;40:423-431. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393157/

Balasubramaniam S, Duley JA, Christodoulou J. Inborn errors of pyrimidine metabolism: clinical update and therapy. J Inherit Metab Dis. 2014;37:687-698. https://www.ncbi.nlm.nih.gov/pubmed/25030255

Bailey CJ. Orotic aciduria and uridine monophosphate synthase: a reappraisal. J Inherit Metab Dis. 2009;1:227-233. https://www.ncbi.nlm.nih.gov/pubmed/19562503

Nyhan WL. Disorders of purine and pyrimidine metabolism. Mol Genet Metab. 2005;86:25-33. https://www.ncbi.nlm.nih.gov/pubmed/16176880

INTERNET

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:258900; Last Update: 04/29/2024. Available at: https://www.omim.org/entry/258900 Accessed August 11, 2025.

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Programs & Resources

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MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

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