What Is Orotic Aciduria?
It is an autosomal recessive disorder that is caused due to mutations in the UMPS gene. There are 15 known patients diagnosed with hereditary orotic aciduria so far. Infants with this condition develop hematological (blood-related) disorders, neurological delays, genitourinary problems, etc.
There are two types of orotic aciduria-
Type 1 - This is the most common type and is caused due to deficiency in both actions performed by the uridine monophosphate synthetase (UMPS) gene.
Type 2 - It is an extremely rare condition that is caused by alterations in the two mechanisms performed by the UMPS gene- deficiency in orotidine 5’-phosphate decarboxylase (ODC) and increased activity of orotate phosphoribosyltransferase (OPRT).
Since it is inherited in a recessive manner, the possibility of having an affected child is 25 percent.
Once the diagnosis is confirmed with genetic testing, treatment is done with Uridine Triacetate (Xuriden) which has been recently approved by the Food and Drug Administration (FDA).
What Causes Orotic Aciduria?
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It is caused by mutations in the UMPS gene and transmitted by autosomal recessive inheritance. The normal version of this gene produces two enzymes- ODC and OPRT. Both of these enzymes are needed to convert orotic acid to uridine monophosphate. The entire process of synthesizing uridine monophosphate takes place in six steps; the OPRT and the ODC are responsible for steps 5 and 6.
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After formation, the uridine monophosphate undergoes decarboxylation (removal of carbon atom) to form uridine- which is the first pyrimidine to be synthesized in the body. Uridine is needed for the synthesis of DNA (deoxyribonucleic acid), RNA (ribonucleic acid), membrane constituents, and glycosylation.
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The UMPS gene is located on the 3q13 chromosome; mutations at two specific points in this gene will lead to the deficiency of ODC and OPRT. As a result, steps 5 and 6 will take place at a reduced pace, leading to the accumulation of orotic acid in the body. The excess orotic acid will be passed through the urine, causing orotic aciduria.
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The uridine that is supposed to be synthesized by these enzymes is produced in very fewer quantities and, by extension, the end products that are dependent on uridine.
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This leads to a cascade of anomalies that reduce the quality of life of the affected individual.
What Is Autosomal Recessive Inheritance?
Autosomal inheritance refers to the transmission of genes from the 22 autosomal chromosomes (excluding one sex chromosome). These are inherited at equal rates among both genders.
Autosomal inheritance is of two types based on the expression of the genetic trait - Dominant and recessive. In autosomal dominant diseases, the condition will be expressed even if the individual receives one (either mother or father) copy of the dominant trait.
In autosomal recessive diseases, the condition will be only expressed when two copies (one from the mother and the father) are inherited. Orotic aciduria is transmitted through autosomal recessive inheritance.
What Are the Symptoms of Orotic Aciduria?
The extent of the symptoms depends on the type of mutation in the UMPS gene; the mutation can cause a protein that may be inefficient, faulty, overproduced, or absent. The symptoms depend on the type and extent of the mutation; the commonly seen symptoms are-
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Megaloblastic Anemia - It is a condition where the bone marrow produces red blood cells that are immature, large, and structurally abnormal, also known as megaloblasts. The lifespan of these megaloblasts is very less compared to the 120 days of normal red blood cells. This leads to megaloblastic anemia.
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Neurological Symptoms - These are present in some infants and children affected by orotic aciduria; they include developmental delays, mild intellectual disability, and seizures.
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Failure to Thrive - Individuals suffering from orotic aciduria do not grow normal weight and height for their age and gender.
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Genitourinary Symptoms - The urine of these patients is cloudy in appearance due to the presence of orotic acid crystals. This phenomenon is known as crystalluria. These orotic acid crystals will also cause obstruction in the urine flow leading to obstructive uropathy and hematuria (blood in the urine).
Other symptoms include diarrhea, stomatitis (inflammation of the mouth and lips), strabismus (malalignment of the eyes), and congenital heart diseases (including septal defects).
How Is Orotic Aciduria Diagnosed?
Orotic aciduria cannot be diagnosed based on symptoms alone because similar symptoms can also be seen in conditions like urea cycle disorders, mitochondrial diseases, lysinuric protein intolerance, Rett syndrome, etc.
After obtaining a detailed family history of the patient, the clinician will request the following laboratory studies-
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Urine Test - Patients with orotic aciduria will have elevated levels of orotic acid; this is also observed in patients with urea cycle disorders, which is where the next test comes into the picture.
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Blood Chemistry - This particular test measures the ammonia levels in the blood; patients with orotic aciduria will have normal ammonia levels. However, patients with urea cycle disorders will have elevated levels of ammonia.
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Complete Blood Count - The characteristic megaloblasts can be observed through this test; some patients might also have associated leukopenia (reduced leukocytes).
The above test will only help with the initial diagnosis of orotic aciduria; the definitive diagnosis can be obtained only through genetic testing. This will detect the mutations in the UMPS gene responsible for the condition.
What Is the Treatment for Orotic Aciduria?
It is treated by-
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Uridine Monophosphate Supplementation - In patients with orotic aciduria, uridine supplementation helps to reduce the symptoms. It is given as uridine 5’- monophosphoric acid, which is a stable form of uridine that can pass the digestive system and cross the blood-brain barrier.
Optimal doses of this supplement have been known to improve memory, stem-cell function, acetylcholine (a neurotransmitter) synthesis, etc.
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Xuriden - Also known as uridine triacetate, it is an FDA-approved drug for orotic aciduria. During clinical trials, it has been known to reduce orotic acid levels and
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Genetic Counseling - It is an educational process that provides information and advice to individuals and families about the genetic condition affecting them. Orotic aciduria is transmitted through autosomal recessive inheritance.
Knowing about the transmission of the condition will help individuals make informed decisions about reproduction and health-related issues.
Conclusion
Orotic aciduria is an extremely rare genetic condition that is caused due to mutation in the UMPS gene. Symptoms include megaloblastic anemia, crystalluria, failure to thrive, etc. Initial diagnosis can be done with laboratory tests followed by genetic testing for a more definite diagnosis. Treatment includes uridine monophosphate and Xuriden supplementation, along with genetic counseling.
