Summary about Disease
Orotic aciduria is a rare, inherited metabolic disorder characterized by an excessive accumulation of orotic acid in the urine. This happens because of a deficiency in one or more enzymes involved in the de novo synthesis of pyrimidines (building blocks of DNA and RNA). The main consequences are impaired growth, anemia, and sometimes, neurological problems. It exists in two forms: Type I (deficiency in both orotate phosphoribosyltransferase and orotidylate decarboxylase) and Type II (deficiency only in orotidylate decarboxylase).
Symptoms
Common symptoms include:
Megaloblastic anemia (abnormally large, immature red blood cells)
Growth retardation
High levels of orotic acid in the urine (orotic acid crystalluria)
Failure to thrive
Less common: Neurological abnormalities (e.g., developmental delay, seizures)
Possible immunodeficiency (increased susceptibility to infections)
Causes
Orotic aciduria is caused by mutations in the UMPS gene. This gene provides instructions for making the UMP synthase enzyme, which has two enzymatic activities: orotate phosphoribosyltransferase and orotidylate decarboxylase. Mutations in *UMPS* gene result in non-functional or partially functional enzymes, leading to the accumulation of orotic acid. It is inherited in an autosomal recessive pattern, meaning both parents must carry a copy of the mutated gene for a child to be affected.
Medicine Used
The primary treatment is oral uridine supplementation. Uridine is a pyrimidine nucleoside that bypasses the blocked enzymatic step in pyrimidine synthesis. It effectively suppresses endogenous pyrimidine production, thereby reducing orotic acid levels. It also helps to reverse the anemia and promote normal growth. Triacetyluridine is sometimes used as well, as it may have better absorption.
Is Communicable
No, orotic aciduria is not communicable. It is a genetic disorder and cannot be spread from person to person.
Precautions
Genetic Counseling: Families with a history of orotic aciduria should seek genetic counseling to understand the risk of recurrence in future pregnancies.
Dietary Management: While uridine supplementation is the mainstay of treatment, a balanced diet is crucial for overall health and growth.
Monitoring: Regular monitoring of blood counts, growth parameters, and orotic acid levels is necessary to adjust the uridine dosage and monitor the effectiveness of the treatment.
Avoidance of Folic Acid Supplementation alone: Giving folic acid to a patient with megaloblastic anemia due to orotic aciduria without giving uridine might mask the problem, but will not solve the pyrimidine deficiency.
How long does an outbreak last?
Orotic aciduria is not an "outbreak" disease like an infection. It is a chronic condition that persists throughout life. Symptoms can be managed with medication. If left untreated, the symptoms are also chronic.
How is it diagnosed?
Diagnosis typically involves:
Urine Orotic Acid Measurement: Elevated levels of orotic acid in the urine are a key diagnostic indicator.
Blood Tests: Complete blood count (CBC) to identify megaloblastic anemia.
Enzyme Assays: Measuring the activity of orotate phosphoribosyltransferase and orotidylate decarboxylase in blood cells or cultured fibroblasts (if available).
Genetic Testing: Molecular genetic testing of the UMPS gene to confirm the diagnosis and identify the specific mutation.
Timeline of Symptoms
Symptoms can appear in infancy or early childhood. The timeline is variable.
Infancy/Early Childhood: Failure to thrive, megaloblastic anemia, and/or presence of orotic acid crystals in the diaper are often the first signs.
Later Childhood (if untreated): Continued growth retardation, persistent anemia, and potential neurological problems may become more apparent.
With treatment: Uridine therapy can significantly improve or reverse symptoms, especially if started early.
Important Considerations
Early Diagnosis: Early diagnosis and treatment are critical to prevent long-term complications, especially growth retardation and neurological deficits.
Lifelong Treatment: Uridine supplementation is typically a lifelong treatment.
Adherence to Treatment: Consistent adherence to uridine therapy is essential for maintaining symptom control.
Individual Variability: The severity of symptoms and response to treatment can vary among individuals with orotic aciduria.
Monitoring for Side Effects: Side effects from uridine are generally rare, but monitoring is still important. Diarrhea and mild gastrointestinal upset are the most common reported side effects.