NORD gratefully acknowledges William L. Nyhan, MD, PhD, Distinguished Professor, Pediatrics, School of Medicine, University of California San Diego, for assistance in the preparation of this report.
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 failure to thrive, susceptibility to infection, and orotic acid crystals in the urine (crystalluria) resulting from excretion of orotic acid in the urine. Impaired neurological development has been observed, but invariably, especially since a treatment has become available.
Because so few individuals have been identified with this disorder, much about hereditary orotic aciduria is not fully understood. The disorder is caused by variations in the UMPS gene. In 2015, the U.S. Food and Drug Administration (FDA) approved a treatment called uridine triacetate (Xuriden) for this disorder.
Some affected infants develop megaloblastic anemia, a condition in which the bone marrow produces unusually large, structurally-abnormal, immature red blood cells (megaloblasts). Megaloblastic anemia usually becomes apparent within the first few months of life.
Some infants and children may have neurological problems including delays in reaching developmental milestones (developmental delays). There may also be delays or issues with intellectual development including mild intellectual disability. Seizures (epilepsy) have been reported in some individuals. Some infants fail to gain weight and grow as they normally would for their age and gender (failure to thrive), but others are normal. As all children grow older, height and weight appear to fall in the normal range.
Sometimes, the urine of people with hereditary orotic aciduria is cloudy because of the presence of orotic acid crystals (crystalluria). These crystals may also play a role in episodes of obstructive uropathy that have can also occur. Obstructive uropathy is a condition in which there is some type of obstruction of the urinary tract, which can cause urine to back up, lead to blood to appear in the urine (hematuria), and other complications.
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).
Hereditary orotic aciduria is caused by variations 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 particular 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 de novo 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 a variation in the UMPS gene, affected individuals have very low levels of the enzyme needed to break down orotic acid. This causes orotic acid to buildup in the body. Some of this excess orotic acid is passed through the urine. In addition to being broken down in the pyrimidine biosynthesis pathway, orotic acid is also believed 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 in order to create a useful product like a specific protein.
There are reports in the medical literature of individuals who have a variation in the UMPS gene, but have only developed very mild symptoms that did not cause any significant consequences. 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.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits the same variant gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, 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 defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Hereditary orotic aciduria is an extremely rare disorder that affects both men and women. 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.
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.
Clinical Testing and Workup
Examination of the urine (urinalysis) can reveal elevated levels of orotic acid. Other conditions, namely 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.
Most affected individuals have had their diagnosis confirmed through molecular genetic testing. Molecular genetic testing can detect variations in the UMPS gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
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 defect, affected individuals cannot create (synthesize) sufficient amounts of 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 weight or height growth. Researchers believe that affected individuals must remain on this treatment throughout their lives to assure 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, gotten 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 treatment would be direct toward the specific symptoms that are present in each individual. Genetic counseling can be of benefit for affected individuals and their families.
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Genetic and Rare Diseases Information Center. Orotic aciduria type 1. September 13, 2017. Available at: https://rarediseases.info.nih.gov/diseases/5429/orotic-aciduria-type-1 Accessed July 15, 2018.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:258900; Last Update:10/17/2016. Available at: https://www.omim.org/entry/258900 Accessed July 15, 2018.
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